High LET Radiation: A Novel Strategy to Overcome Tumor Microtubes -Mediated Radioresistance in Glioblastoma

Tumor cell networks formed by tumor microtubes (TMs) may play a key role in the development of therapy resistance in glioblastoma (GB). TM-mediated detoxification from radiation-induced reactive oxygen species (ROS) may infer radioresistance. We hypothesize that high linear energy transfer (LET) radiation, which describes the amount of energy deposited by radiation per unit length, interacts directly with the DNA backbone to induce complex lesions and thus might be less dependent on TM-mediated resistance mechanisms. Therefore, we sought to systematically investigate the impact of LET-induced complex DNA damage on TM formation and GB survival. To this end, the formation of TMs, radiation-induced nuclear DNA damage repair foci (RIF), and GB survival were correlated with a gradual increase in LET using a dose series of clinical protons (low), helium (intermediate), and carbon (high) ion beams. Consistent with conventional photon/X-rays, low-LET proton irradiation promoted TM formation in a dose-dependent manner. In contrast, an anti-correlation between LET and TM induction was found, i.e., a decreased network connectivity with gradual increase of LET and formation of complex DNA damage. Consequently, LET increase correlated with reduced cell survival, with the most pronounced cell killing observed after high-LET carbon irradiation. Moreover, the inverse correlation between LET and TM density was further confirmed for a broad range of LET modulated within the carbon ion irradiation spectrum. This is the first report on the relevance of LET as a novel mean to overcome TM network-mediated radioresistance in GB, with ramifications for the clinical translation of high-LET particle radiotherapy to further improve outcome in this still devastating disease.